Anorectal Manometry in 3D NEW! - Swiss-knife.org

54.19
Gene chip analysis of A20 expressing livers following extended liver Resection uncovers its multiple
targets that promote liver repair and regeneration
P. Studer 1,2 , C. da Silva 2 , C. Longo 2 , M. Bhasin 2 , T. Libermann 2 , D. Inderbitzin 1 , D. Candinas 1 , D. Stroka 1 ,
C. Ferran 2 ( 1 Berne, 2 Boston/USA)
Objective: The NFkB inhibitory protein A20 promotes hepatoprotection through combined anti-inflammatory,
anti-apoptotic, anti-oxidative and pro-proliferative functions. We have shown that overexpression
of A20 significantly improves liver recovery and survival in mouse models of extended (78%) and
lethal radical (87%) hepatectomy (Hx) as well as in a model of total liver ischemia reperfusion injury.
The aim of this study was to unravel the molecular targets of A20 in the liver.
Methods: We extracted total mRNA from rAd.beta-gal and rAd.A20 transduced mouse livers, before
and 24 h following extended Hx. Two GeneChip arrays (Affymetrix) were probed with RNA pooled from
3 mice per group and time-point. A rray images were analyzed by dChip. Genes were considered differentially
expressed when 90% of the lower confidence bound of the fold change was above two.
Venn Diagrams helped evaluating the impact of 78% Hx and that of A20 overexpression. Results were
analyzed using Ingenuity software.
Results: The major pathways affected by A20 included cell cycle, apoptosis, fatty acid metabolism,
IL-6 and IFN signaling and antigen presentation. A20 impacts these pathways in a manner that favors
protection from apoptosis/necrosis, heightened proliferation, decreased inflammation, dampened immune
response and improved metabolic control. Several targets were validated in vitro and in vivo,
by gain and loss (A20 -/- and A20+/-) of functions studies. One of the most manifest findings in A20
expressing livers was decreased expression of the cell cycle break, Cyclin Dependent Kinase Inhibitor
p21waf1, and increased expression of the suppressor of cytokine signaling-3 which enhances IL-6
proliferative signals. Another seminal finding was A20-dependent upregulation of peroxisome proliferator
activated receptor alpha, modulating FXR/RXR signaling, thereby modulating lipid metabolism
and providing anti-oxidant and anti-inflammatory advantages. Other A20 targets within the IFN and
antigen presentation pathways are being validated. All these effects of A20 were noted before and
maintained after Hx.
Conclusion: These results unravel the multiple protective targets of A20 in the liver that are all modulated
in a way that provides a determining advantage to achieve success in liver transplantation. The
mechanisms by which A20 affects so many downstream genes in the liver is being investigated.
Thoracic Surgery – Posters 55
55.1
Photodynamic therapy selectively enhances liporubicin uptake in sarcoma metastasis to rodent lungs
J. Y. Perentes, C. Cheng, E. Debefve, A. Haouala, S. Andrejevic Blant, T. Krueger, J.-P. Ballini, S. Peters,
L. Decosterd, H. van den Bergh, H.-B. Ris (Lausanne)
Objective: In specific conditions, photodynamic therapy (PDT) can enhance the distribution of macromolecules
across the endothelial barrier of solid tumors. It was recently postulated that tumor neovessels
are more responsive to PDT than the normal vasculature. We thus hypothesized that Visudyne ® -
mediated PDT would selectively increase liposomal doxorubicin (liporubicin TM ) distribution in sarcoma
metastasis to rodent lungs while sparing the normal surrounding tissue.
Methods: Sarcoma tumors were generated sub-pleurally in the lungs of fifty-four Fischer rats. Ten days
following sarcoma implantation, tumors underwent different pre-treatment schemes: no PDT (control),
low dose PDT (0.0625 mg/kg Visudyne ® , 10J/cm 2 and 35 mW/cm 2 ) and high- dose PDT (0.125 mg/
kg Visudyne ® , 10J/cm 2 and 35 mW/cm 2 ). liporubicin TM was then administered intravenously and allowed
to circulate for three or six hours. At the end of each treatment scheme, we assessed the uptake
of liporubicin TM in tumor and lung tissues by high performance liquid chromatography and fluorescence
microscopy.
Results: In all PDT-treated animals, there was a significant enhancement of liporubicin TM uptake in tumors
compared to controls after 3 and 6 hours of drug circulation time. In addition, liporubicin TM distribution
within the normal lung tissue was, however, not affected by PDT. Thus, PDT pre-treatment significantly
enhanced the ratio of tumor-to-lung drug uptake compared to controls. Finally, fluorescence
microscopy revealed a well detectable doxorubicin signalling in PDT treated tumors but not in controls.
Conclusion: PDT is a tumor-specific enhancer of liporubicin TM distribution in sarcoma lung metastasis
which may find a translation in clinics.
55.2
Volumetric measurement of disease extend in malignant pleural mesothelioma (MPM) to assess
therapy response
I. Opitz, M. Tutic, T. Frauenfelder, R. Götti, A. Schramm, W. Weder, B. Marincek, R. Stahel (Zürich)
Objective: The purpose of this study was to assess robustness of volumetric measurement of malignant
pleural mesothelioma (MPM) compared to modified RECIST.
Methods: 30 patients (mean age 60) with known MPM where included in the study. All patients underwent
CT before and after 3 cycles of platinol-based induction chemotherapy to evaluate therapy
response. Modified RECIST criteria and tumor volumetric approach were applied on each CT exam
as was the tumor volume using dedicated software (Myrian, Intrasense, France). Modified RECISTcriteria
were independently assessed by three readers having both exams of each patient simultaneously
available. Progressive disease (PD) was defined as >30% increase in the sum of unidimensional
tumor measurements, >20% decrease as partial response (PR), -20% - +30% as stable disease (SD).
The tumor volume was independently measured by three readers. Interobserver agreement for tumor
response and interclass correlation were assessed for both methods.
Results: The determination of uni-dimensional tumor measurement revealed a low inter-rater reliability
(0.55) and a low interobserver agreement for tumor response classification (general kappa 0.33).
Only 14 patients were classified identically. A high inter-rater reliability (0.99) and interobserver agreement
(general kappa 0.9) was found for absolute tumor volumes. 27 cases were classified identical.
The number of cases classified as “stable disease” and “progressive disease” was higher for volumetry
approach using tumor equivalent criteria and modified RECIST identical criteria, respectively.
Conclusion: Volumetric measurement of the MPM is accurate and highly reproducible to evaluate
therapy response. The interobserver agreement is very high in comparison to modified RECIST criteria.
55.3
Surgery is a valuable treatment option for selected patients with metastatic lung cancer
S. Collaud, S. Hillinger, D. Schneiter, P. Kestenholz, W. Weder (Zürich)
Objective: Patients with distant metastases of lung cancer are generally not considered for surgery and
faced a poor prognostic. However published results suggest long-term survival in carefully selected patients.
The aim of our study was to assess the outcome of patients with lung cancer and synchronous
single-organ metastasis who underwent bifocal therapy including lung resection.
Methods: 169 patients underwent diagnostic or therapeutic surgical procedures for metastatic lung
cancer in our institution between 2002 and 2008. Retrospective chart review was performed and 33
patients with synchronous single-organ metastatic lung cancer treated with bifocal therapy were included
in this study. Synchronous metastasis was defined as a disease-free interval of two months
or less. Bifocal therapy was defined as a surgical and/or radiation therapy for the metastatic site as
well as a surgical resection of the primary. Six wedge resections, two segmentectomy, 17 lobectomy,
five extended lobectomy, one bilobectomy, two extended bilobectomy and two right pneumonectomy
were performed to treat the primary tumor. Microscopic complete resection (R0) was completed in 30
patients (91%). Six patients (18%) received an induction treatment before lung surgery. 11 patients
(33%) had an adjuvant treatment. Metastatic sites were brain in 20 (61%), lung in six (18%), bone
in two (6%), adrenal in two (6%), and other in three (9%) patients. 25 patients (76%) had a solitary
metastasis, while eight (24%) had two to three metastasis.
Results: At last follow-up, 15 patients were free of tumor. A local recurrence (intrathoracic and/or at the
metastatic site) occured in five patients. A distant recurrence occurred in six patients, while a combined
local and distal recurrence was diagnosed in two patients. No data were available for five patients.
1- and 3-year survivals for the overall population were 50% and 32%, respectively. Recurrence rate at
1 and 3 years were 42% and 28%. The univariate analysis identified R resection status and pathologic
tumor extension (pT) as prognostic factors for tumor recurrence and survival, respectively.
Conclusion: Surgery is an option in the treatment of patient with synchronous single-organ metastatic
lung cancer in selected cases.
55.4
Predicting survival after resection of pulmonary metastases from colorectal cancer: a history of previous
liver metastases matters
P. Gervaz, U. Landes, J. Robert, G. Mentha, V. Ott, Ph. Morel (Genève)
Objective: A minority of patients with lung metastases (LM) from colorectal cancer (CRC) is candidate
for surgical therapy with a curative intent. However, there is currently no possibility to identify those patients
who may benefit the most from lung resection. The aim of this study was to identify parameters
associated with prolonged survival after resection of LM from CRC.
Methods: We performed a retrospective analysis of 40 successive patients (median age 63 [range
33-82] years) who underwent resection of LM from CRC in a single institution from 1990 to 2008.
Results: Median follow-up was 33 (range 4-139) months. Sixteen (40%) patients had a prior hepatectomy
for liver metastases before undergoing lung surgery. Median disease-free interval between
primary colorectal tumor and development of lung metastases was 32.5 months. For the whole group,
3- and 5-year overall survival after thoracotomy was 70.1 and 43.4%, respectively. In multivariate
analysis, two variables were correlated with tumor recurrence after thoracotomy; a history of previous
liver metastases (HR=3.8, 95%CI 1.4-9.8); and lung surgery other than wedge resection (HR=3.0,
95%CI 1.1-7.8). Prior presence of liver metastases was also correlated with an increased risk of death
(HR=5.1, 95% CI 1.1-24.8, p=0.04). Median survival after thoracotomy was 87 (range 34-139) months
in the group of patients without liver metastases versus 40 (range 28-51) months in patients who had
prior hepatic metastases (log-rank test, p=0.09).
Conclusion: The main parameter associated with poor survival after lung resection of CRC metastases
is a history of liver metastases.
55.5
Acute allograft rejection in orthotopic mouse lung transplants - a scanning electron microscopy study
A. Draenert, J. Jungraithmayr, W. Weder (Zürich)
Objective: Acute rejection (AR) continues to be a major barrier to graft acceptance after lung transplantation
(Tx). AR episodes are characterized by mononuclear inflammation targeting small vessels and
bronchioles of the transplant. Due to the three - dimensional structure of alveoli and bronchioles, the
scanning electron microscopy (SEM) proved to be the method of choice to evaluate these histo-pathological
changes. Using an orthotopic single lung transplantation mouse model, this study focuses on
the early changes of the transplant compared to the contra-lateral native lung.
Methods: The orthotopic lung Tx mouse model was employed, using C57BL/6 mouse strain as recipient,
and Balb/c as donor. At time of harvest (day 1 and 5), explanted lungs were flushed and perfused
with glutaraldehyde via the pulmonary artery and the trachea. After preparation under the light micro-
swiss knife 2010; 7: special edition 49